Histone-lysine ''N''-methyltransferase 2A, also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia 1 (MLL1), or zinc finger protein HRX (HRX), is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''KMT2A''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
MLL1 is a histone
methyltransferase deemed a positive global regulator of
gene transcription. This protein belongs to the group of
histone-modifying enzymes comprising
transactivation domain 9aaTAD
[; ; ] and is involved in the
epigenetic
In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...
maintenance of transcriptional memory. Its role as an epigenetic regulator of neuronal function is an ongoing area of research.
Function
Transcriptional regulation
KMT2A gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and
hematopoiesis
Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
. The encoded protein contains multiple conserved functional domains. One of these domains, the
SET domain, is responsible for its
histone H3
Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal end, N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'b ...
lysine 4 (H3K4) methyltransferase activity which mediates
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...
modifications associated with epigenetic transcriptional activation. Enriched in the nucleus, the MLL1 enzyme trimethylates H3K4 (
H3K4me3
H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addit ...
). It also upregulates mono- and dimethylation of H3K4. This protein is processed by the enzyme
Taspase 1 into two fragments, MLL-C (~180 kDa) and MLL-N (~320 kDa). These fragments then assemble into different multi-protein complexes that regulate the transcription of specific target genes, including many of the
HOX genes
Hox genes, a subset of homeobox genes, are a group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals. Hox proteins encode and specify the characteristics of 'position', ensuring that the c ...
.
Transcriptome profiling after deletion of MLL1 in cortical neurons revealed decreased promoter-bound H3K4me3 peaks at 318 genes, with 31 of these having significantly decreased expression and promoter binding.
Among them were ''
Meis2'', a homeobox transcription factor critical for development of forebrain neurons and ''
Satb2'', a protein involved in neuronal differentiation.
Multiple chromosomal translocations involving this gene are the cause of certain
acute lymphoid leukemias and
acute myeloid leukemia
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
s. Alternate splicing results in multiple transcript variants.
Cognition and emotion
MLL1 has been shown to be an important epigenetic regulator of complex behaviors. Rodent models of MLL1 dysfunction in forebrain neurons showed that conditional deletion results in elevated anxiety and defective cognition.
Prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...
-specific knockout of MLL1 results in the same phenotypes, as well as working memory deficits.
Stem cells
MLL1 has been found to be an important regulator of
epiblast-derived stem cells, post-implantation epiblast derived stem cells which display pluripotency yet many recognizable differences from the traditional
embryonic stem cell
Embryonic stem cells (ESCs) are Cell potency#Pluripotency, pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-Implantation (human embryo), implantation embryo. Human embryos reach the blastocyst stage 4� ...
s derived from inner cell mass prior to implantation. Suppression of MLL1 expression was shown to be adequate for inducing ESC-like morphology and behavior within 72 hours of treatment. It has been proposed that the small molecule inhibitor MM-401, which was used to inhibit MLL1, changes the distribution of
H3K4me1
H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.
Nomenclature
H3K4me1 i ...
, the single
methylation
Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...
of the
histone H3
Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal end, N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'b ...
lysine 4, to be significantly downregulated at MLL1 targets thus leading to decreased expression of MLL1 targets, rather than a direct regulation of pluripotency core markers.
Structure
Gene
KMT2A gene has 37
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence i ...
and resides on
chromosome 11 at q23.
Protein
KMT2A has over a dozen binding partners and is cleaved into two pieces, a larger
N-terminal fragment, involved in gene repression, and a smaller
C-terminal fragment, which is a transcriptional activator.
The cleavage, followed by the association of the two fragments, is necessary for KMT2A to be fully active. Like many other
methyltransferases, the KMT2 family members exist in multisubunit nuclear complexes (human COMPASS), where other subunits also mediate the enzymatic activity.
Clinical significance
Abnormal H3K4 trimethylation has been implicated in several neurological disorders such as autism.
Humans with cognitive and neurodevelopmental disease often have dysregulation of H3K4 methylation in
prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...
(PFC) neurons.
It also may participate in the process of
GAD67 downregulation in
schizophrenia
Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
.
MLL1 is required for the expression of
senescence-associated secretory phenotype (SASP)-related genes and promotes increased inflammation.
Rearrangements of the MLL1 gene are associated with aggressive acute
leukemia
Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
s, both lymphoblastic and myeloid.
Despite being an aggressive leukemia, the MLL1 rearranged sub-type had the lowest mutation rates reported for any cancer.
Mutations in MLL1 cause
Wiedemann-Steiner syndrome and
acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is a cancer of the Lymphocyte, lymphoid line of blood cells characterized by the development of large numbers of lymphoblast, immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, ...
.
The leukemia cells of up to 80 percent of infants with ALL-1 have a chromosomal rearrangement that fuses the MLL1 gene to a gene on a different chromosome.
Interactions
MLL (gene) has been shown to
interact with:
*
ASH2L,
*
CREBBP,
*
CTBP1,
*
HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. ...
,
*
HCFC1,
*
MEN1,
*
PPIE,
*
PPP1R15A
Protein phosphatase 1 regulatory subunit 15A, also known as growth arrest and DNA damage-inducible protein (GADD34), is a protein that in humans is encoded by the ''PPP1R15A'' gene
In biology, the word gene has two meanings. The Mendelian g ...
,
*
RBBP5,
and
*
WDR5.
References
Further reading
*
*
*
*
*
External links
MLL OMIM Entry:MYELOID/LYMPHOID OR MIXED LINEAGE LEUKEMIA GENE; MLL
*
on the
Atlas of Genetics and Oncology
{{Transcription factors, g0
Epigenetics
Proteins
Transcription factors
Human proteins